rs10509305

Positions:

• chr10-68885620-A-C
• chr10-68885620-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_152709.5(STOX1):​c.1824A>C​(p.Glu608Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,614,008 control chromosomes in the GnomAD database, including 37,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2875 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34580 hom.)
• Consequence: STOX1 NM_152709.5 missense
• Clinical Significance: Benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: -1.56

Genes affected

STOX1 (HGNC:23508): (storkhead box 1) Enables RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in several processes, including positive regulation of G2/M transition of mitotic cell cycle; positive regulation of protein phosphorylation; and regulation of gene expression. Located in centrosome; cytosol; and nuclear lumen. Implicated in pre-eclampsia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005174637).
• BP6: Variant 10-68885620-A-C is Benign according to our data. Variant chr10-68885620-A-C is described in ClinVar as [Benign]. Clinvar id is 1720.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-68885620-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STOX1	NM_152709.5	c.1824A>C	p.Glu608Asp	missense_variant	3/4	ENST00000298596.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STOX1	ENST00000298596.11	c.1824A>C	p.Glu608Asp	missense_variant	3/4	1	NM_152709.5	P4

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26816 AN: 152074 Hom.: 2866 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0991

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.219 AC: 54508 AN: 249390 Hom.: 6565 AF XY: 0.220 AC XY: 29723 AN XY: 135298

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.0816

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.213 AC: 312084 AN: 1461816 Hom.: 34580 Cov.: 36 AF XY: 0.215 AC XY: 156424 AN XY: 727212

Gnomad4 AFR exome AF: 0.0535

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.176 AC: 26835 AN: 152192 Hom.: 2875 Cov.: 32 AF XY: 0.180 AC XY: 13393 AN XY: 74392

Gnomad4 AFR AF: 0.0591

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.0993

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.177

Alfa AF: 0.209 Hom.: 8311

Bravo AF: 0.169

TwinsUK AF: 0.208 AC: 772

ALSPAC AF: 0.211 AC: 812

ESP6500AA AF: 0.0583 AC: 225

ESP6500EA AF: 0.215 AC: 1779

ExAC AF: 0.212 AC: 25628

Asia WGS AF: 0.202 AC: 700 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.218

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Preeclampsia/eclampsia 4 Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_152709.4:c.1824A>C in the STOX1 gene has an allele frequency of 0.307 in European (Finnish) subpopulation in gnomAD dacabase. 7171 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.06, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0070
DANN	Benign	0.090
DEOGEN2	Benign	0.0072	T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.051	N
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.96	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.98	T;T;.
Sift4G	Benign	0.68	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.016
MutPred		0.35		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MPC		0.064
ClinPred		0.0042	T
GERP RS		1.1
Varity_R		0.041
gMVP		0.024

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10509305; hg19: chr10-70645376; COSMIC: COSV53813997;